Spike binds Spike inhibitors

Stable Identifier
R-HSA-9707827
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Compartment
ReviewStatus
5/5
Locations in the PathwayBrowser
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SVG |   | PPTX  | SBGN
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SARS‑CoV‑2 infection begins with the binding of viral S (spike) protein to the host's cell surface angiotensin converting enzyme 2 (ACE2), depending on the presence of heparan sulfate proteoglycans (HSPGs), and endocytosis of the bound virion. Inhibiting this interaction might be useful in treating patients with COVID-19. A genetically modified soluble form of ACE2, called hrsACE2 (alunacedase alfa), may decrease cell entry of SARS-CoV-2 competing for membrane-bound ACE2, therby minimizing lung injury and multiple organ dysfunction (Zoufaly et al. 2020, El-Aziz et al. 2020). In vitro studies shows that hrsACE2 reduces viral growth of SARS-CoV-2 by a factor of 1000–5000 in cell-culture, engineered human blood vessels and kidney organoids (Monteil et al. 2020). High affinity miniprotein inhibitors LCB1 and LCB3 have been shown to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein and block SARS-CoV-2 infection of Vero E6 cells (Cao et al. 2020). These novel inhibitors are suggested to act as viral traps and inactivators of the spike protein.

In November 2020 the FDA granted an emergency use authorization (EUA) to bamlanivimab/etesevimab, a combination of two IgG1 monoclonal antibodies directed against the spike protein of SARS-CoV-2. In a trial they showed a statistically significant reduction in viral load at day 11 (Gottlieb et al, 2021). Both were isolated from convalescent patients (Shi et al, 2020; Jones et al, 2021).

Inhibition of Spike binding to the heparan sulfate moieties of HSPGs prevents SARS-CoV-2 cell entry via ACE2, possibly by several mechanisms (Partridge et al, 2021; Paiardi et al, 2022). Heparin is an approved and widely used anticoagulant. Unfractioned heparin binds to the S1/S2 site of Spike and has a 150-fold higher antiviral effect against SARS-CoV-2 in vitro than low-molecular-weight heparin (LMWH) (Clausen et al, 2020; Kim et al, 2020; Mycroft-West et al, 2020; Liu et al, 2021; Tree et al, 2021). Several clinical studies with nebulised unfractionated heparin (UFH) are ongoing (NCT04545541, NCT04723563, NCT04635241).
Mitoxantrone is an approved neoplastic agent; it binds cell surface heparan sulfate and strongly inhibited SARS-CoV-2 cell entry with an IC50 more than 100-fold lower than that of cytotoxicity (Zhang et al, 2020). Spike protein stability depends on disulfide bonds which can be destabilized by thiol/disulfide‐reactive compounds. N‐acetylcysteine, L‐ascorbic acid, and JTT‐705 efficiently inhibited binding of S to ACE2 in vitro and inhibited pseudoviral infection in mice (Manček‐Keber et al, 2021). Although a few clinical trials tested NAC and ascorbic acid no final assessments are available.
Literature References
PubMed ID Title Journal Year
32454512 A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2

Duan, X, Chen, Z, Wang, L, Gao, GF, Huang, W, Song, T, Yuan, Z, Song, J, Bi, X, Zhang, Y, Yan, J, Wu, G, Shi, R, Wu, L, Wang, FS, Shan, C, Tong, Z, Zhang, B, Liu, P, Han, C, Qi, J, Liu, WJ, Feng, H, Gao, G, Hu, X, Wang, Q

Nature 2020
33125711 Unfractionated heparin inhibits live wild type SARS-CoV-2 cell infectivity at therapeutically relevant concentrations

Page, CP, Wilkinson, T, Lima, MA, Elmore, MJ, Coombes, N, Yates, EA, Buttigieg, KR, Carroll, MW, Yang, Z, Karlsson, R, Staples, KJ, Chen, YH, Mycroft-West, CJ, Tree, JA, Hogwood, J, Spalluto, CM, Turnbull, JE, Gray, E, Skidmore, MA, Singh, D

Br J Pharmacol 2021
33820835 The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in nonhuman primates

Geisbert, TW, Westendorf, K, Berens, SJ, Tycho, SA, Hendle, J, Collins, DW, Pellacani, D, Jepson, KR, Corbett, KS, Muthuraman, K, Mulligan, MJ, Graham, BS, Heinz, BA, Balasubramaniam, D, Samanovic, MI, Mascola, JR, Jones, BE, Hinshaw, SJ, Johnson, NV, de Vries, M, Cross, RW, Abiona, O, Dittmann, M, Brown-Augsburger, PL, Kraft, L, Borisevich, V, Davies, J, Baric, RS, Barnhart, BC, Pustilnik, A, Yang, ES, Adams, AC, McLellan, JS, Cujec, TP, Zhang, Y, Piper, MH, Mohamed, A, Wang, L, Hwang, Y, Wiethoff, CM, Martinez, DR, Hsieh, CL, Goya, R, Hansen, CL, Falconer, E, Foster, D, Sobhanifar, S, Bidshahri, R, Smith, MA, Higgs, RE, Wrapp, D, Blackbourne, JL, Triana, FJ, Goldsmith, JA, Žentelis, S, Belli, HM, Xiang, P

Sci Transl Med 2021
32653452 Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions

Linhardt, RJ, Zhang, F, Woods, RJ, Fu, L, Sood, A, Kim, SY, Jin, W, Montgomery, DW, Fuster, MM, Grant, OC, Dordick, JS

Antiviral Res 2020
33475701 Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial

Nirula, A, Chen, P, Shen, L, Mocherla, B, Schade, AE, Kallewaard, NL, Cardona, J, Oakley, G, Custer, KL, Morris, J, Ebert, PJ, Patel, DR, Heller, B, Adams, AC, Skovronsky, DM, Boscia, J, Holzer, TR, Sabo, J, Stosor, V, Kumar, P, Van Naarden, J, Higgs, RE, Shawa, I, Gottlieb, RL, Durante, M, Huhn, G, Klekotka, P

JAMA 2021
34200372 ACE2-Independent Interaction of SARS-CoV-2 Spike Protein with Human Epithelial Cells Is Inhibited by Unfractionated Heparin

Urwin, L, James, DC, Partridge, LJ, Green, LR, Monk, PN, Nicklin, MJH

Cells 2021
33368089 Heparin Inhibits Cellular Invasion by SARS-CoV-2: Structural Dependence of the Interaction of the Spike S1 Receptor-Binding Domain with Heparin

Yates, EA, Guimond, SE, Vicenzi, E, Li, Y, Miller, GJ, Forsyth, NR, Rudd, TR, Clementi, M, Nader, HB, Elli, S, Skidmore, MA, Nunes, QM, Pagani, I, Lima, MA, Ferro, V, Guerrini, M, Su, D, Meneghetti, MCZ, Mycroft-West, CJ, Bisio, A, Fernig, DG, Turnbull, JE, Procter, P, Gandhi, NS, Mancini, N

Thromb Haemost 2020
33131609 Human recombinant soluble ACE2 in severe COVID-19

Wenisch, C, Haider, D, Puchhammer-Stoeckl, E, Pawelka, E, Grieb, A, Penninger, JM, Aberle, JH, Neuhold, S, Slutsky, AS, Montserrat, N, Poglitsch, M, Traugott, M, Bergthaler, A, Stiasny, K, Mirazimi, A, Zhang, H, Zoufaly, A, Seitz, T, Hoepler, W, Laferl, H

Lancet Respir Med 2020
34235261 Heparan Sulfate Proteoglycans as Attachment Factor for SARS-CoV-2

Bouwman, KM, Tompkins, SM, Boons, GJ, de Vries, RP, Liu, L, Chopra, P, Wolfert, MA, Li, X

ACS Cent Sci 2021
34929169 The binding of heparin to spike glycoprotein inhibits SARS-CoV-2 infection by three mechanisms

Wade, RC, Paiardi, G, Urbinati, C, Oreste, P, Richter, S, Rusnati, M

J Biol Chem 2022
32333836 Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2

Monteil, V, Penninger, JM, Montserrat, N, Slutsky, AS, Kwon, H, Romero, JP, Leopoldi, A, Wimmer, RA, Stahl, M, Prado, P, Conder, R, Hagelkrüys, A, Hurtado Del Pozo, C, Mirazimi, A, Zhang, H, Prosper, F, Wirnsberger, G, Garreta, E

Cell 2020
33144565 Human recombinant soluble ACE2 (hrsACE2) shows promise for treating severe COVID-19

Stockand, JD, Abd El-Aziz, TM, Al-Sabi, A

Signal Transduct Target Ther 2020
34004056 Disruption of disulfides within RBD of SARS-CoV-2 spike protein prevents fusion and represents a target for viral entry inhibition by registered drugs

Plaper, T, Jazbec, V, Pichlmair, A, Govednik, T, Lainšček, D, Jerala, R, Hafner-Bratkovič, I, Bencina, M, Orehek, S, Grass, V, Bergant, V, Manček-Keber, M

FASEB J 2021
32907861 De novo design of picomolar SARS-CoV-2 miniprotein inhibitors

Carter, L, Veesler, D, Chen, RE, Strauch, EM, Baker, D, Kozodoy, L, Diamond, MS, Stewart, L, Coventry, B, Walls, AC, Park, YJ, Miller, L, Goreshnik, I, Case, JB, Cao, L

Science 2020
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